While cocaine use in adolescents appears to be on the decline, use in individuals 35 years and older has increased as has the amount consumed by heavy users. Cocaine abuse will likely continue to be a major public health concern for the foreseeable future. Research into the effects of cocaine on the brain has increased significantly over the last decade. In spite of increased scientific investigation, the basic brain mechanisms responsible for compulsive cocaine use are still not clearly defined. Although dopamine appears to have an important role in these processes, therapeutic approaches based on this premise have been disappointing. It is clear that even rodents, the basic brain processes underlying compulsive cocaine use involve complex neuronal circuits and networks that include a number of neurohumors including dopamine. This research project proposes continued investigation of these complex brain processes using a rat self-administration model and neurobiological methodologies that will further knowledge of these underlying processes. Microdialysis, neurotransmitter turnover rate measures and membrane homogenate binding methodologies will be used to further investigate the neuronal systems responsible for the acquisition and maintenance of cocaine self- administration. Neurotransmitter turnover rate assessments of the biogenic amine and selective amino acid neurohumors will be completed in 28 brain regions of intravenous cocaine self-administering and in yoked-cocaine and yoked-vehicle infused controls. The involvement of cholinergic neurons will be investigated by measuring the turnover rates of acetylcholine and muscarinic cholinergic receptor binding in brain regions of rats self- injecting cocaine and in yoked cocaine and yoked vehicle infused controls. The involvement of dopamine, serotonin and GABA neurons will be further characterized using microdialysis in rats responding on schedules of concurrent food and intravenous cocaine. Data from these experiments should add to understanding the actions of cocaine on cholinergic, dopaminergic, serotonergic and GABAergic neurons as they relate to intravenous self-administration. Elucidation of the circuits that initiate and mediate compulsive cocaine use will not only be beneficial to understanding drug abuse, but also to understanding basic brain-behavior interactions.